Process for producing fenofibrate tablets

ABSTRACT

The invention provides processes using suspensions to produce fenofibrate compositions. The resulting fenofibrate compositions can be made in the form of a capsule.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/665,520 filed Sep. 22, 2003, which is a continuation of U.S.application Ser. No. 10/288,425 filed Nov. 6, 2002, issued as U.S. Pat.No. 6,652,881; which is a continuation of U.S. application Ser. No.10/126,875 filed Apr. 22, 2002, issued as U.S. Pat. No. 6,589,552; whichis a continuation of U.S. application Ser. No. 10/078,500 filed Feb. 21,2002, issued as U.S. Pat. No. 6,596,317; which is a continuation of U.S.application Ser. No. 09/899,026 filed Jul. 6, 2001, issued as U.S. Pat.No. 7,037,529; which is a continuation of U.S. application Ser. No.09/572,330 filed May 18, 2000, issued as U.S. Pat. No. 6,277,405; whichis a continuation of U.S. application Ser. No. 09/005,128 filed Jan. 9,1998, issued as U.S. Pat. No. 6,074,670; which claims priority to FrenchApplication No. 97 00 479 filed Jan. 17, 1997. This application is alsoa continuation of U.S. application Ser. No. 10/290,333 filed Nov. 8,2002, issued as U.S. Pat. No. 7,041,319.

BACKGROUND OF THE INVENTION

The present invention relates to a novel pharmaceutical compositionhaving high bioavailability through improved dissolution, and a methodfor preparing it. The invention more particularly relates to apharmaceutical composition for administration by oral route, containingan active ingredient of poor aqueous solubility.

Numerous active ingredients suffer from the disadvantage of being poorlysoluble in an aqueous medium, thus having an insufficient dissolutionprofile and, consequently, poor bioavailability within the organism,following oral administration. The therapeutic dose required to beadministered must thus be increased in order to obviate thisdisadvantage. This particularly applies to numerous hypolipemiant activeingredients, such as those belonging to the fibrate family.

Fenofibrate is a well-known hypolipemiant from the family of fibrates,which is commercially available in various doses (100 and 300 mg forexample Secalip®) but in a form leading to poor bioavailability of theactive ingredient. Indeed, due to it poor hydrosolubility, fenofibrateis poorly absorbed in the digestive tract and consequently itsbioavailability is incomplete, irregular and often varies from oneperson to another.

To improve the dissolution profile of fenofibrate and itsbioavailability, thereby reducing the dose requiring to be administered,it would be useful to increase its dissolution so that it could attain alevel close to 100%.

Moreover, for patient comfort, it is advantageous to seek a dosage formthat only requires the medicament to be taken once daily while givingthe same effect as one administered several times daily.

EP-A-0330532 discloses a method for improving bioavailability offenofibrate. This patent describes the effect of co-micronizingfenofibrate with a surfactant, for example sodium laurylsulfate in orderto improve fenofibrate solubility and thereby increase itsbioavailability. This patent teaches that co-micronizing fenofibratewith a solid surfactant improves fenofibrate bioavailability to a muchgreater extent than the improvement that would be obtained either byadding a surfactant, or through solely micronizing the fenofibrate, or,yet again, through intimately mixing the fenofibrate and surfactant,micronized separately. The dissolution method employed is theconventional rotating blade technique (European Pharmacopoeia): productdissolution kinetics are measured in a fixed volume of the dissolutionmedium, agitated by means of a standardized device; a test was alsocarried out with an alternative technique to the European Pharmacopoeia,using the continuous-flow cell method.

The process of EP-A-0330532 leads to a new dosage form in which theactive ingredient, co-micronized with a solid surfactant, has improvedfenofibrate dissolution, and thus increased bioavailability, which makesit possible, for a given level of effectiveness, to decrease the dailydose of the medicament: respective 67 mg and 200 mg instead of 100 mgand 300 mg.

However, the preparation method in that patent is not completelysatisfactory inasmuch as it does not lead to complete bioavailability ofthe active ingredient, and suffers from several disadvantages. Thetechnique of co-micronizing fenofibrate with a solid surfactant does, itis true, improve dissolution of the active ingredient, but thisdissolution remains, however, incomplete.

There is thus a need to improve fenofibrate bioavailability in order toattain, over very short periods of time, a level close to 100% (or, inany case, better than the following limits: 10% in 5 minutes, 20% in 10minutes, 50% in 20 minutes and 75% in 30 minutes in a medium consistingof 1200 ml water to which 2% Polysorbate 80 is added, or of 1000 ml ofwater to which 0.025M sodium lauryl sulfate sodium is added, with ablade rotation speed of 75 rpm), and this even when dissolution mediahaving a low surfactant content are used.

Applicant has found that, surprisingly, it is possible to resolve thisproblem by a new method for preparing a pharmaceutical composition byspraying a suspension of the active ingredient onto an inerthydrosoluble carrier. The present invention also relates topharmaceutical compositions thus prepared.

The use is already known of a polymer, such as polyvinylpyrrolidone forproducing tablets, in concentrations of the order of 0.5 to 5% byweight, at a maximum 10% by weight. In this case, thepolyvinylpyrrolidone is used as a binder. Similarly, the use of apolymer such as hydroxymethylpropylmethyl cellulose as a granulationbinder is known. Thus, European patent application 0,519,144 disclosespellets of a poorly soluble substance, omeprazole, obtained by sprayinga dispersion or suspension of the active ingredient in a solutioncontaining said polymer onto inert pellets in a fluidized-bedgranulator. However, here again, the polymer (HPMC and HPC) is only usedas a granulation binder, in an amount of about 50% by weight, based onthe weight of the active ingredient, which, bearing in mind the presenceof the inert pellets of a large size (about 700 μm) and the overallfinal weight leads to final active ingredient and polymer contents whichare very low, of the order of barely a few percent based on the weightof the final covered pellet. Finally, it will be noted that the size ofthe inert pellets in this documents is fairly large, which, in the caseof fenofibrate, would lead to a final formulation having a volume whichis much too large for ready oral administration.

The use of polymer, such as polyvinylpyrrolidone for manufacturing“solid dispersions” is also known, obtained in general byco-precipitation, co-fusion or liquid-phase mixing followed by drying.What we have here is fixation of the active ingredient in isolatedmicroparticles on the polyvinylpyrrolidone, which avoids problems ofpoor wetting of the solid and re-agglomeration of the particles. Thearticle “Stable Solid Dispersion System Against Humidity” by Kuchiki etal., Yakuzaigaku, 44 No. 1, 31-37 (1984) describes such a technique forpreparing solid dispersions using polyvinylpyrrolidone. The amounts ofPVP here are very high, and the ratio between the active ingredient andPVP are comprised between 1/1 and 1/20. In the case however there is noinert carrier.

WO-A-96 01621 further discloses a sustained release composition,comprising an inert core (silica in all examples) coated with a layerwhich contains the active ingredient in admixture with a hydrophilicpolymer, the weight ratio active ingredient/polymer being comprisedbetween 10/1 and 1/2 and the weight ratio active ingredient/inert corebeing comprised between 5/1 and 1/2, with an outer layer to impart thesustained release property. These compositions can be compressed. Thehydrophilic polymer can be polyvinylpyrrolidone. This document alsodiscloses a process for preparing said composition; for example in afluidized-bed granulator one will spray a dispersion of activeingredient in a polymer solution onto the inert cores. This documentsolely relates to sustained release compositions, the technical problemto be solved being the compression, without damages, of the outer layerimparting the sustained release property.

Nevertheless, nothing in the state of the art teaches nor suggest thepresent invention.

SUMMARY OF THE INVENTION

Thus, the present invention provides an immediate-release fenofibratecomposition comprising:

(a) an inert hydrosoluble carrier covered with at least one layercontaining a fenofibrate active ingredient in a micronized form having asize less than 20 μm, a hydrophilic polymer and, optionally, asurfactant; said hydrophilic polymer making up at least 20% by weight of(a); and

(b) optionally one or several outer phase(s) or layer(s).

In one embodiment, a surfactant is present with the active ingredientand the hydrophilic polymer.

The invention also provides a composition comprising fenofibrate havinga dissolution of at least 10% in 5 minutes, 20% in 10 minutes, 50% in 20minutes and 75% in 30 minutes, as measured using the rotating blademethod at 75 rpm according to the European Pharmacopoeia, in adissolution medium constituted by water with 2% by weight polysorbate 80or in a dissolution medium constituted by water with 0.025M sodiumlauryl sulfate.

A method for preparing a pharmaceutical composition is also provided,comprising the steps of:

(a) preparing a fenofibrate suspension in micronized form with aparticle size below 20 μm, in a solution of hydrophilic polymer and,optionally surfactant;

(b) applying the suspension from step (a) to an inert hydrosolublecarrier;

(c) optionally, coating granules thus obtained with one or severalphase(s) or layer(s).

Step (b) is preferably carried out in a fluidized-bed granulator.

The method can comprise a step in which products obtained from step (b)or (c) are compressed, with or without additional excipients.

The invention also provides a suspension of fenofibrate in micronizedform having a size less than 10 μm, in a solution of hydrophilic polymerand, optionally, surfactant.

The invention will be described in more detail in the description whichfollows, with reference to the attached drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of a comparative study of the dissolution profile of acomposition according to the invention, compared to that of Lipanthyl®200M;

FIG. 2 is a graph illustrating a comparative study of the dissolutionprofile of a composition according to the invention and that ofpharmaceutical products commercially available on the German market.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The expression “in micronized form” in this invention means a substancein a particulate form, the dimensions of the particles being less thanor equal to about 20 μm.

Advantageously, this dimension is less than or equal to 10 μm.

In the framework of this invention, the expression “inert hydrosolublecarrier” means any excipient, generally hydrophilic, pharmaceuticallyinert, crystalline or amorphous, in a particulate form, not leading to achemical reaction under the operating conditions employed, and which issoluble in an aqueous medium, notably in a gastric acid medium. Examplesof such excipients are derivatives of sugars, such as lactose,saccharose, hydrolyzed starch (malto-dextrine), etc. Mixture are alsosuitable. The individual particle size of the inert hydrosoluble carriercan be, for example, between 50 and 500 micron.

The expression “hydrophilic polymer” in the invention should be taken tomean any high molecular weight substance (greater, for example, than300) having sufficient affinity towards water to dissolve therein andform a gel. Examples of such polymers are polyvinylpyrrolidone,poly(vinyl alcohol), hydroxypropylcellulose, hydroxymethylcellulose,hydroxypropylmethylcellulose, gelatin, etc. Polymer blends are alsosuitable.

The preferred hydrophilic polymer is polyvinylpyrrolidone (PVP). The PVPused in this invention has, for example, a molecular weight comprisedbetween 10,000 and 100,000, preferably for example between 20,000 and55,000.

The term “surfactant” is used in its conventional sense in thisinvention. Any surfactant is suitable, whether it be amphoteric,non-ionic, cationic or anionic. Examples of such surfactants are: sodiumlauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate oranother ester of polyoxyethylene sorbitane, sodium dioctylsulfosuccinate(DOSS), lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol,polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides,Poloxamer®, etc. Mixtures of surfactants are also suitable.

The preferred surfactant is sodium laurylsulfate, which can beco-micronized with fenofibrate.

The compositions according to the invention can additionally contain anyexcipient conventionally used in the pharmaceutical and chemical fieldswhich is compatible with the active ingredient, such as binders,fillers, pigments, disintegrating agents, lubricants, wetting agents,buffers, etc. As examples, excipients able to be used in this inventionwe can cite: microcrystalline cellulose, lactose, starch, colloidalsilica, talc, glycerol esters, sodium stearyl fumarate, titaniumdioxide, magnesium stearate, stearic acid, cross-linked polyvinylpyrrolidone (AC DI SOL®), carboxymethyl starch (Explotab®, Primojel®),hydroxypropylcellulose, hydroxymethylcellulose,hydroxypropylmethylcellulose, gelatin, etc.

Here, the expression “outer phase or layer” should be taken to mean anycoating on the element (a) with the active ingredient (forming a“core”). Indeed, it can be useful to have available one or severalphase(s) or layer(s) on top of the coated core. The invention thuscovers a single core with one layer, but also several cores in a phase,as is the case of tablets which are formed from “cores” mixed with aphase.

This outer layer comprises conventional excipients.

It is also possible to provide a layer comprising additives, for themanufacture of tablets. In this embodiment, the outer layer comprises adisintegration agent and, for example, a lubricant; the thus covered andmixed granules can then be readily compressed and easily disintegrate inwater.

The compositions according to the invention comprise, in general, basedon the total composition weight excluding the outer phase or layer, aninert hydrosoluble carrier making up from 10 to 80% by weight,preferably 20 to 50% by weight, the fenofibrate representing from 5 to50% by weight, preferably from 20 to 45% by weight, the hydrophilicpolymer representing from 20 to 60% by weight, preferably 25 to 45% byweight, the surfactant making up from 0 to 10% by weight, preferably 0.1to 3% by weight.

The outer layer or phase if present, can make up to 80% by weight of thetotal weight, preferably up to 50% by weight.

The hydrophilic polymer represents preferably more than 25% by weight,based on the weight of (a).

The weight ratio of fenofibrate/hydrophilic polymer can for example becomprised between 1/10 and 4/1, preferably, for example, between 1/2 and2/1.

When a surfactant is employed, the weight ratio surfactant/hydrophilicpolymer can be comprised for example between 1/500 and 1/10, preferably,for example, between 1/100 and 5/100.

In one embodiment, the composition according to the invention takes theform of tablets.

This tablet preferably results from the compression of elements (a)(under the form of granules) together with an outer phase.

In another embodiment, the composition of the invention takes the formof granules enclosed inside a capsule, for example in gelatin, or insidea bag.

The compositions of the invention are particularly suitable foradministering active ingredients by oral route.

The composition according to the invention is prepared by a novelprocess comprising spraying a suspension of the active ingredient in amicronized form in a solution of a hydrophilic polymer and, optionally,a surfactant, onto the inert core.

When a surfactant is present, the active ingredient can be co-micronizedwith the surfactant. One will then use with advantage the teachings ofEP-A-0330532.

The method according to the invention consists in using the fluidizedbed granulation principle, but with specific starting materials, inorder to arrive at an improved dissolution profile and thus, at elevatedbioavailability. In particular, the invention employs a suspension ofthe micronized active ingredient in a solution of a hydrophilic polymerand, optionally, a surfactant.

The fluidized-bed granulation technique is widely used in thepharmaceutical industry for preparing capsules or tablets.Conventionally, according to the prior art, a powder or a mixture ofpowders (active ingredient+excipients) is put into suspension in thefluidized bed in a granulator, and a solution containing a binder and,optionally, a surfactant, is sprayed onto this bed to form granules. Thefluidized-bed granulation technique is well known to those skilled inthe art and reference should be made to standard works such as forexample “Die Tablette”, by Ritschel, Ed. Cantor Aulendorf, pages211-212.

The invention, as has been indicated, comprises spraying a suspension ofan active ingredient micronized with a hydrophilic polymer onto an inertcarrier. Following granulation, the granulate formed consists ofcrystals of, for example, lactose, which are isolated (or possiblyagglomerated together by the spray solution) and particles of activeingredient and PVP adhering to the crystal surface. The granule couldsimilarly be constituted of coated crystals which are agglomerated, oreven of such an agglomerate having received a coating.

The compositions according to the invention can also be prepared byother methods, for example by spraying a solution of the micronizedactive ingredient onto the hydrosoluble inert carrier.

The granulates thus obtained can, if desired, be provided with an outercoating or compressed into tablets, or form agglomerates.

The outer layer or layer is/are applied using conventional coatingtechniques such as coating in a pan or fluidized bed coater.

When the granulate obtained (whether subsequently coated or not) iscompressed to form tablets, this step can be implemented using anyconventional technique which is suitable, for example using analternating or rotating compressing equipment.

The significant starting product is the suspension of the activeingredient. This suspension is prepared by putting the micronized activeingredient into suspension in a solution comprising the hydrophilicpolymer and, optionally, a surfactant, in solution in a solvent. If asurfactant is employed, it is put into solution in the solvent(beaker+magnetic or vane stirrer). Next, the hydrophilic polymer (PVP)is dispersed, while stirring, in the solution previously obtained.Depending on polymer solubility, this either dissolves in the solutionor forms a gel or a suspension having varying degrees of thickness.While still stirring, the micronized active ingredient is dispersed inthe form of a fine shower into the above solution or suspension, to forma homogeneous suspension. The order of these steps can be reversed. Thesolvent employed can be aqueous or organic (for example ethanol). Forexample demineralized water can be used.

The active ingredient concentration in the suspension is from 1 to 40%by weight, preferably from 10 to 25%.

The hydrophilic polymer concentration in the suspension is from 5 to 40%by weight, preferably 10 to 25%.

The surfactant concentration in the suspension is from 0 to 10% byweight, preferably below 5%.

The invention also covers this novel suspension.

Without wishing to be tied down to a specific theory, applicant believesthat this novel method, through the use of a micronized activeingredient suspension in a hydrophilic polymer solution, enabled a novelcomposition to be obtained in which the active ingredient is in anon-re-agglomerated form.

The following examples illustrate the invention without limiting it.

EXAMPLE 1

Preparation of a pharmaceutical composition of fenofibrate according tothe invention.

A composition containing, as the element a), micronized fenofibrate,Plasdone®, Capsulac® and sodium lauryl sulfate was prepared.

The micronized fenofibrate had a particle size of about 5 μm, asmeasured using a Coulter counter.

The Plasdone K25® corresponds to a polyvinylpyrrolidone PVP ISP and theCapsulac 60® corresponds to a coarse crystal lactose monohydrate(Meggle) (particle size between 100 and 400 μm).

The sodium laurylsulfate (7 g) is dissolved in water (demineralizedwater, 1750 g) and the micronized fenofibrate (350 g) is put intosuspension in the mixture obtained (for example using a helix stirrer at300 rpm for 10 minutes, then using an Ultra Turrax agitator at 10,000rpm, for 10 minutes). Following this, the PVP (350 g) is added whilestill agitating, stirring (helix stirrer) being continued until thelatter had dissolved (30 minutes). It is all passed through a sieve (350μm) to eliminate possible agglomerates.

Separately, the lactose (400 g) is put into suspension in a fluidizedair bed granulator (of the Glatt® GPCG1—Top Spray type or equivalent)and heated to a temperature of 40° C.

The fenofibrate suspension is sprayed onto the lactose. This step iscarried out under the following conditions: spraying pressure: 2.1 bar,air throughput 70 m³/h, air inlet temperature: 45° C.; air outlettemperature: 33° C.; product temperature 34° C.; duration of spraying: 3h.

The granulate thus obtained can be put inside capsules or transformedinto tablets. Any suitable conventional technique for preparing suchdosage forms can be used.

For transformation to tablet form, one will mix 191 g of the granulateobtained (using for example a mixer-grinder type mixing apparatus, aplanetary mixer or turn-over mixer), with the outer phase having thefollowing composition:

-   -   56 g Polyplasdone XL® (cross-linked polyvinylpyrrolidone ISP, as        described in the USA Pharmacopoeia “USP-NF” under the name of        crospovidone, mean molecular weight>1,000,000);    -   88 g Avicel® PH200 (microcrystalline cellulose);    -   3.5 g sodium stearyl fumarate (Mendell, U.S.A.); and    -   2 g Aerosil® 200 (colloidal silica).

The cross-linked polyvinylpyrrolidone, the microcrystalline cellulose,the sodium stearyl fumarate and the colloidal silica are respectively,disintegration agents, binders, lubricating and flow enhancing agents.

The tablet can be obtained on an alternating compression machine (forexample Korsch EKO) or a rotary machine (for example Fette Perfecta 2).

One thus obtains tablets having the following composition, expressed inmg:

-   element (a):

micronized fenofibrate 100.0 PVP 100.0 Lactose 114.3 sodiumlaurylsulfate 2.0

-   outer phase (or layer):

cross-linked PVP 92.7 microcrystalline cellulose 145.7 sodium stearylfumarate 5.8 colloidal silica 3.3

EXAMPLE 2

Dissolution of a composition according to the invention and acomposition according to the prior art.

-   a) dissolution medium and procedure for measuring dissolution.

A dissolution medium which is discriminating, in other words one inwhich two products having very different dissolution profiles in gastricjuices will have very different dissolution curves is looked for.

For this, an aqueous medium containing a surfactant, this beingPolysorbate 80 (polyoxyethylene sorbitane mono-oleate) is used. Thissurfactant is readily available from various suppliers, is the object ofa monograph in the Pharmacopoeias, and is thus easy to implement (beingalso a water-soluble liquid product). Other surfactants can also beused.

The rotating blade method (European Pharmacopoeia) is used under thefollowing conditions: volume of medium: 1200 ml; medium temperature: 37°C.; blade rotation speed: 75 rpm; samples taken: every 2.5 minutes.Determination of the amount dissolved is carried out byspectrophotometry. Test are repeated 6 times over.

-   b) Results

The composition according to the invention consisted of two tabletscontaining about 100 mg fenofibrate prepared according to Example 1.

The prior art composition was Lipanthyl® 200M from LaboratoiresFournier, containing 200 mg fenofibrate (corresponding to capsules of200 mg fenofibrate, co-micronized with sodium laurylsulfate, andcontaining lactose, pre-gelatinized starch, cross-linkedpolyvinylpyrrolidone and magnesium stearate, in line with the teachingsof EP-A-0330532).

The results obtained are shown graphically in FIG. 1, on which thepercentage of dissolution is shown, the observed standard deviationbeing indicated between brackets.

These results clearly show that the compositions according to theinvention have a dissolution profile which is distinctly better thanthat of the prior art compositions.

These results also clearly show that with the compositions of theinvention, the standard deviation observed is distinctly lower than isthe case with prior art compositions.

EXAMPLE 3

Study of bioavailability of compositions according to the invention andprior art compositions.

A test of bioavailability on healthy volunteers was carried out.

The following compositions were tested:

-   -   composition according to the invention: capsules containing        granules prepared according to example 1, containing 200 mg        fenofibrate.    -   first composition according to the prior art: Lipanthyl® 200M        from Laboratoires Fournier, containing 200 mg fenofibrate,        identical to that in the previous example.    -   second prior art composition: Secalip® in capsule form (300 mg        fenofibrate in the form of three 100 mg capsules).

The study was carried out on 6 healthy volunteers receiving a singledose of fenofibrate, with a minimum 6-day rest period betweenadministrations. The samples for pharmaco-kinetic analysis werecollected after each administration at the following times: 0.5 h; 1 h;2 h; 3 h; 4 h; 5 h; 6 h; 8 h; 10 h; 12 h; 24 h; 36 h; 48 h; 72 h; and 96hours following administration of the medicament. Fenofibric acidcontent in plasma was measured for each sample.

The results obtained are given in table 1 below.

TABLE 1 dose Cmax tmax t ½ AUC 0–t AUC 0–∞ Product (mg) (μg/ml) (h) (h)(μg · h/ml) (μg · h/ml) Invention 200 5.4 6 23 148 162 Secalip ® 100 3 ×100 1.1 25 39 53 56 Lipanthyl ® 200 1.6 8.3 41 71 92 200M Cmax: maximumplasma concentration tmax: time to reach Cmax t ½: plasma halflife AUC0–t: area under the curve from 0 to t AUC 0–∞: area under the curve from0 to ∞.

The results clearly show that the compositions of the present inventionhave a dissolution profile that is an improvement over compositions ofthe prior art, leading to a considerably enhanced bioavailability of theactive ingredient compared to that obtained with compositions of theprior art.

EXAMPLE 4

Comparison of the dissolution profile of compositions according to theinvention and that of products currently on the German market.

On the German market, immediate or sustained-release fenofibrateformulations exist. Like in France, the 100 mg and 300 mg (conventional)forms coexist with 67 and 200 mg forms (having enhanced bioavailability,according to the teaching of EP-A-0330532). These products are asfollows:

-   Fenofibrate—ratiopharm; Ratiopharm—Ulm;

Capsules;

Composition: 100 mg fenofibrate;

Excipients: lactose, corn starch, magnesium stearate, E 171 colorant,gelatine.

-   Durafenat; Durachemie—Wolfratshausen Capsules;

Composition: 100 mg fenofibrate;

Excipients: lactose, corn starch, magnesium stearate, E 171 colorant,gelatine.

-   Normalip pro; Knoll—Ludwigshafen;

Capsules;

Composition: 200 mg Fenofibrate;

Excipients: Crospovidone, gelatine, monohydrate lactose, magnesiumstearate, corn starch, sodium laurylsulfate, E 132 and E 171 colorants.

A comparison was made between:

-   -   the tablet of the invention as prepared using example 1 (2×100        mg)    -   Normalip Pro® (200 mg);    -   Lipanthyl® 200M (200 mg) (according to the preceding example);    -   Fenofibrate by Ratiopharm® (2×100 mg);    -   Durafenat® (2×100 mg)

The tests were implemented under the same conditions as in the previousexamples. FIG. 2 summarizes the results.

These results clearly show that the compositions of the invention have adistinctly improved dissolution compared to prior art compositions.

Obviously, the present invention is not limited to the embodimentsdescribed but may be subject to numerous variations readily accessibleto those skilled in the art.

1. A process for producing a capsule comprising fenofibrate, wherein theprocess comprises: (i) preparing an aqueous suspension comprising atleast one hydrophilic polymer and fenofibrate particles in micronizedform having a particle size of less than 20 μm, wherein one hydrophilicpolymer is a polyvinylpyrrolidone with a molecular weight between 20,000and 100,000; (ii) spraying the suspension onto inert carriers to formgranulates; and (iii) enclosing the granulates inside the capsule. 2.The process of claim 1, wherein step (i) of preparing the suspensioncomprises (a) preparing a solution comprising at least one hydrophilicpolymer and (b) adding the fenofibrate to the solution to produce thesuspension.
 3. The process of claim 1, wherein step (i) of preparing thesuspension comprises (a) preparing a solution comprising at least onehydrophilic polymer by dissolving the hydrophilic polymer and (b) addingthe fenofibrate to the solution to produce the suspension.
 4. Theprocess of claim 1, wherein step (i) of preparing the suspensioncomprises (a) adding the fenofibrate to a solution to form thesuspension, and (b) dissolving at least one hydrophilic polymer in thesuspension.
 5. The process of claim 1, wherein the suspension furthercomprises at least one surfactant.
 6. The process of claim 1, whereinthe suspension comprises fenofibrate and hydrophilic polymer in a weightratio of fenofibrate/hydrophilic polymer between 1/10 and 4/1.
 7. Theprocess of claim 1, wherein the suspension comprises fenofibrate andhydrophilic polymer in a weight ratio of fenofibrate/hydrophilic polymerbetween 1/2 and 2/1.
 8. The process of claim 1, wherein the fenofibratehas a particle size less than 10 μm.
 9. The process of claim 1, whereinthe suspension comprises fenofibrate in an amount from 1 to 40% byweight.
 10. The process of claim 9, wherein the suspension comprisesfenofibrate in an amount from 10 to 25% by weight.
 11. The process ofclaim 1, wherein the suspension comprises the hydrophilic polymer in anamount from 5 to 40% by weight.
 12. The process of claim 11, wherein thesuspension comprises the hydrophilic polymer in an amount from 10 to 25%by weight.
 13. The process of claim 1, wherein the at least onehydrophilic polymer further comprises; a poly(vinyl alcohol), ahydroxypropylcellulose, a hydroxy-methylcellulose, ahydroxypropylmethylcellulose, a gelatin, or a mixture of two or morethereof.
 14. The process of claim 5, wherein the suspension comprisesthe surfactant in an amount of up to 10% by weight.
 15. The process ofclaim 14, wherein the suspension comprises the surfactant in an amountof up to 5% by weight.
 16. The process of claim 5, wherein thesuspension comprises surfactant and hydrophilic polymer in a weightratio of surfactant/hydrophilic polymer between 1/500 and 1/10.
 17. Theprocess of claim 5, wherein the suspension comprises surfactant andhydrophilic polymer in a weight ratio of surfactant/hydrophilic polymerbetween 1/100 and 5/100.
 18. The process of claim 5, wherein thesurfactant is sodium lauryl sulfate, monooleate, monolaurate,monopalmitate, monostearate or another ester of polyoxyethylenesorbitane, sodium dioctylsulfosuccinate, lecithin, stearylic alcohol,cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil,polyoxyethylene fatty acid glycerides, poloxamer, or a mixture of two ormore thereof.
 19. The process of claim 18, wherein the surfactant issodium lauryl sulfate.
 20. The process of claim 1, wherein the inertcarriers are inert hydrosoluble carriers.
 21. The process of claim 1,which further comprises, between steps (ii) an (iii), mixing thegranulates with at least one pharmaceutical excipient.
 22. The processof claim 21, wherein the pharmaceutical excipient is selected from thegroup consisting of at least one binder, at least one filler, at leastone pigment, at least one disintegrating agent, at least one lubricant,at least one wetting agent, at least one buffer, and a mixture of two ormore thereof.
 23. The process of claim 21, wherein the pharmaceuticalexcipient is selected from the group consisting of microcrystallinecellulose, lactose, starch, colloidal silica, talc, glycerol esters,sodium stearyl fumarate, titanium dioxide, magnesium stearate, stearicacid, cross-linked polyvinyl pyrrolidone, carboxymethyl starch,hydroxypropylcellulose, hydroxymethylcellulose,hydroxypropylmethylcellulose, gelatin, and a mixture of two or morethereof.
 24. The process of claim 1, wherein the capsule comprises from5 to 50% by weight fenofibrate, from 10 to 75% by weight carrier, andfrom 20 to 60% by weight hydrophilic polymer.
 25. The process of claim1, wherein the capsule comprises from 20 to 45% by weight fenofibrate,from 20 to 50% by weight carrier, and from 25 to 45% by weighthydrophilic polymer.
 26. The process of claim 24, wherein the capsulefurther comprises up to 10% by weight surfactant.
 27. The process ofclaim 26, wherein the capsule comprises from 0.1 to 3% by weightsurfactant.
 28. A process for producing a capsule comprisingfenofibrate, wherein the process comprises: (i) preparing an aqueoussuspension comprising at least one surfactant, at least one hydrophilicpolymer, and fenofibrate particles in micronized form having a particlesize of less than 20 μm, wherein one hydrophilic polymer is a polyvinylpyrrolidone with a molecular weight between 20,000 and 100,000;(ii) spraying the aqueous suspension onto inert carriers to formgranulates; and (iii) enclosing the granulates inside a capsule.
 29. Theprocess of claim 28, wherein step (i) of preparing the aqueoussuspension comprises (a) preparing an aqueous solution comprising atleast one surfactant and at least one hydrophilic polymer and (b) addingthe fenofibrate to the aqueous solution to produce the aqueoussuspension.
 30. The process of claim 28, wherein step (i) of preparingthe aqueous suspension comprises (a) preparing an aqueous solutioncomprising at least one surfactant and at least one hydrophilic polymerby dissolving said surfactant and hydrophilic polymer and (b) adding thefenofibrate to the aqueous solution to produce the aqueous suspension.31. The process of claim 28, wherein step (i) of preparing the aqueoussuspension comprises (a) dissolving at least one surfactant in anaqueous solution, (b) dissolving at least one hydrophilic polymer in anaqueous solution, and (c) adding the fenofibrate to the aqueous solutionto produce the aqueous suspension.
 32. The process of claim 28, whereinstep (i) of preparing an aqueous suspension comprises (a) dissolving atleast one hydrophilic polymer in an aqueous solution, (b) dissolving atleast one surfactant in an aqueous solution, and (c) adding themicronized fenofibrate to the aqueous solution to form the aqueoussuspension.
 33. The process of claim 28, wherein step (i) of preparingthe aqueous suspension comprises (a) dissolving at least one surfactantin an aqueous solution, (b) adding the fenofibrate to the aqueoussolution to form the aqueous suspension, and (c) dissolving at least onehydrophilic polymer in the aqueous suspension.
 34. The process of claim28, wherein step (i) of preparing the aqueous suspension comprises (a)dissolving at least one hydrophilic polymer in an aqueous solution, (b)adding the fenofibrate to the aqueous solution to form the aqueoussuspension, and (c) dissolving at least one surfactant in the aqueoussuspension.
 35. The process of claim 28, wherein the suspensioncomprises fenofibrate and hydrophilic polymer in a weight ratio offenofibrate/hydrophilic polymer between 1/10 and 4/1.
 36. The process ofclaim 28, wherein the suspension comprises fenofibrate and hydrophilicpolymer in a weight ratio of fenofibrate/hydrophilic polymer between 1/2and 2/1.
 37. The process of claim 28, wherein the fenofibrate has aparticle size less than 10 μm.
 38. The process of claim 28, wherein thesuspension comprises fenofibrate in an amount from 1 to 40% by weight.39. The process of claim 38, wherein the suspension comprisesfenofibrate in an amount from 10 to 25% by weight.
 40. The process ofclaim 28, wherein the suspension comprises the hydrophilic polymer in anamount from 5 to 40% by weight.
 41. The process of claim 40, wherein thesuspension comprises the hydrophilic polymer in an amount from 10 to 25%by weight.
 42. The process of claim 28, wherein the at least onehydrophilic polymer further comprises; a poly(vinyl alcohol), ahydroxypropylcellulose, a hydroxy-methylcellulose, ahydroxypropylmethylcellulose, a gelatin, or a mixture of two or morethereof.
 43. The process of claim 28, wherein the suspension comprisesthe surfactant in an amount of up to 10% by weight.
 44. The process ofclaim 43, wherein the suspension comprises the surfactant in an amountof up to 5% by weight.
 45. The process of claim 28, wherein thesuspension comprises surfactant and hydrophilic polymer in a weightratio of surfactant/hydrophilic polymer between 1/500 and 1/10.
 46. Theprocess of claim 28, wherein the suspension comprises surfactant andhydrophilic polymer in a weight ratio of surfactant/hydrophilic polymerbetween 1/100 and 5/100.
 47. The process of claim 28, wherein thesurfactant is sodium lauryl sulfate, monooleate, monolaurate,monopalmitate, monostearate or another ester of polyoxyethylenesorbitane, sodium dioctylsulfosuccinate, lecithin, stearylic alcohol,cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil,polyoxyethylene fatty acid glycerides, poloxamer, or a mixture of two ormore thereof.
 48. The process of claim 47, wherein the surfactant issodium lauryl sulfate.
 49. The process of claim 28, wherein the inertcarriers are inert hydrosoluble carriers.
 50. The process of claim 28,which further comprises, between steps (ii) and (iii), mixing thegranulates with at least one pharmaceutical excipient.
 51. The processof claim 50, wherein the pharmaceutical excipient is selected from thegroup consisting of at least one binder, at least one filler, at leastone pigment, at least one disintegrating agent, at least one lubricant,at least one wetting agent, at least one buffer, and a mixture of two ormore thereof.
 52. The process of claim 50, wherein the pharmaceuticalexcipient is selected from the group consisting of microcrystallinecellulose, lactose, starch, colloidal silica, talc, glycerol esters,sodium stearyl fumarate, titanium dioxide, magnesium stearate, stearicacid, cross-linked polyvinyl pyrrolidone, carboxymethyl starch,hydroxypropylcellulose, hydroxymethylcellulose,hydroxypropylmethylcellulose, gelatin, and a mixture of two or morethereof.
 53. The process of claim 28, wherein the capsule comprises from5 to 50% by weight of fenofibrate, from 10 to 75% by weight of carrier,from 20 to 60% by weight of hydrophilic polymer, and up to 10% by weightof surfactant.
 54. The process of claim 53, wherein the capsulecomprises from 20 to 45% by weight of fenofibrate, from 20 to 50% byweight of carrier, from 25 to 45% by weight of hydrophilic polymer, andfrom 0.1 to 3% by weight of surfactant.
 55. A process for producing acapsule comprising fenofibrate, wherein the process comprises: (i)preparing an aqueous suspension comprising at least one surfactant, atleast one hydrophilic polymer, and fenofibrate particles in micronizedform having a particle size of less than 20 μm, wherein one hydrophilicpolymer is a polyvinylpyrrolidone with a molecular weight between 20,000and 100,000; by (a) preparing an aqueous solution comprising at leastone surfactant and at least one hydrophilic polymer by dissolving thesurfactant and the hydrophilic polymer and (b) adding the fenofibrateparticles to the solution to produce the aqueous suspension; (ii)spraying the aqueous suspension onto inert carriers to form granulatesand (iii) enclosing the granulates inside a capsule.
 56. The process ofclaim 55, wherein the suspension comprises fenofibrate and hydrophilicpolymer in a weight ratio of fenofibrate/hydrophilic polymer between1/10 and 4/1.
 57. The process of claim 55, wherein the suspensioncomprises fenofibrate and hydrophilic polymer in a weight ratio offenofibrate/hydrophilic polymer between 1/2 and 2/1.
 58. The process ofclaim 55, wherein the fenofibrate has a particle size less than 10 μm.59. The process of claim 55, wherein the suspension comprisesfenofibrate in an amount from 1 to 40% by weight.
 60. The process ofclaim 59, wherein the suspension comprises fenofibrate in an amount from10 to 25% by weight.
 61. The process of claim 55, wherein the suspensioncomprises the hydrophilic polymer in an amount from 5 to 40% by weight.62. The process of claim 61, wherein the suspension comprises thehydrophilic polymer in an amount from 10 to 25% by weight.
 63. Theprocess of claim 55, wherein the at least one hydrophilic polymerfurther comprises; and a poly(vinyl alcohol), a hydroxypropylcellulose,a hydroxy-methylcellulose, a hydroxypropylmethylcellulose, a gelatin, ora mixture of two or more thereof.
 64. The process of claim 55, whereinthe suspension comprises the surfactant in an amount of up to 10% byweight.
 65. The process of claim 64, wherein the suspension comprisesthe surfactant in an amount of up to 5% by weight.
 66. The process ofclaim 55, wherein the suspension comprises surfactant and hydrophilicpolymer in a weight ratio of surfactant/hydrophilic polymer between1/500 and 1/10.
 67. The process of claim 55, wherein the suspensioncomprises surfactant and hydrophilic polymer in a weight ratio ofsurfactant/hydrophilic polymer between 1/100 and 5/100.
 68. The processof claim 55, wherein the surfactant is sodium lauryl sulfate,monooleate, monolaurate, monopalmitate, monostearate or another ester ofpolyoxyethylene sorbitane, sodium dioctylsulfosuccinate, lecithin,stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylenericin oil, polyoxyethylene fatty acid glycerides, poloxamer, or amixture of two or more thereof.
 69. The process of claim 68, wherein thesurfactant is sodium lauryl sulfate.
 70. The process of claim 55,wherein the inert carriers are inert hydrosoluble carriers.
 71. Theprocess of claim 55, which further comprises, between steps (ii) and(iii), mixing the granulates with at least one pharmaceutical excipient.72. The process of claim 71, wherein said pharmaceutical excipient isselected from the group consisting of at least one binder, at least onefiller, at least one pigment, at least one disintegrating agent, atleast one lubricant, at least one wetting agent, at least one buffer,and a mixture of two or more thereof.
 73. The process of claim 71,wherein said pharmaceutical excipient is selected from the groupconsisting of microcrystalline cellulose, lactose, starch, colloidalsilica, talc, glycerol esters, sodium stearyl fumarate, titaniumdioxide, magnesium stearate, stearic acid, cross-linked polyvinylpyrrolidone, carboxymethyl starch, hydroxypropylcellulose,hydroxymethylcellulose, hydroxypropylmethylcellulose, gelatin, and amixture of two or more thereof.
 74. The process of claim 55, wherein thecapsule comprises from 5 to 50% by weight of fenofibrate, from 10 to 75%by weight of carrier, from 20 to 60% by weight of hydrophilic polymer,and up to 10% by weight of surfactant.
 75. The process of claim 55,wherein the capsule comprises from 20 to 45% by weight of fenofibrate,from 20 to 50% by weight of carrier, from 25 to 45% by weight ofhydrophilic polymer, and from 0.1 to 3% by weight of surfactant.